1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of Na V 1.7 inhibition.

Autor: Boezio AA; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States. Electronic address: aboezio@relaytx.com., Andrews K; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Boezio C; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Chu-Moyer M; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Copeland KW; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., DiMauro EF; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Foti RS; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Fremeau RT Jr; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Gao H; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Geuns-Meyer S; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Graceffa RF; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Gunaydin H; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Huang H; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., La DS; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Ligutti J; Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States., Moyer BD; Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States., Peterson EA; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Yu V; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States., Weiss MM; Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jun 15; Vol. 28 (11), pp. 2103-2108. Date of Electronic Publication: 2018 Apr 17.
DOI: 10.1016/j.bmcl.2018.04.035
Abstrakt: Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na V 1.7 and demonstrate high levels of selectivity over other Na V isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective Na V 1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over Na V 1.5 and favorable pharmacokinetics in rodents.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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